Hypothermia therapy has received considerable attention as a treatment for trauma patients who sustain head injuries as well as multiple system injury. Posttraumatic cerebral ischemia occurs frequently and significantly worsens outcome after human head injury. However, hypothermia has not been assessed in a model of traumatic brain injury (TB) with secondary ischemia. We have shown that the traumatized brain is hypersensitive to ischemia in a rodent model of fluid-percussion TBI (FP- TBI) with secondary and nearly complete forebrain ischemia. Our studies also show hippocampal hypersensitivity to posttraumatic forebrain ischemia for 1 to 24 hours after FP-TB1, which is mediated, in part, by excitotoxic mechanisms. Experimental studies suggest that moderate hypothermia (30-33 degree centrigrade) may provide neuroprotection by decreasing excitotoxic damage. We have provided the following evidence for excitotoxic processes after FP-TB1: 1) muscarinic and NMDA receptor antagonists attenuate posttraumatic ischemic hypersensitivity; 2) increased brain excitatory amino acid (EAA) exposure occurs during TBI and secondary ischemia; 3) enhanced hippocampal metabotropic receptor sensitivity to acetylcholine, glutamate, and serotonin, as inferred by increased agonist-induced polyphosphoinositide (PI) turnover, occurs after TBI; 4) significant downregulation of total protein kinase C (PKC) occurs after TBI; 5) hippocampal microinjected staurosporine (a serine-threonine protein kinase inhibitor) or genistein (a tyrosine kinase inhibitor) both attenuate enhanced posttraumatic CA1 ischemic neuronal death. We believe that posttraumatic PKC downregulation may be responsible for this enhanced signal transduction. Two potential consequences of increased signal transduction of these receptor families are enhanced presynaptic neurotransmitter release and postsynaptic neurotransmitter sensitivity dysfunction that may be modulated by hypothermia. We propose that: a) posttraumatic neurotransmitter and ischemic hypersensitivity occur as the result of impaired glutamate receptor- effector downregulation secondary to aberrant protein kinase activation, especially by PKC; b) a therapeutic reduction of posttraumatic neurotransmitter and ischemic hypersensitivity can be achieve with moderate hypothermia. We will test whether: a) enhanced posttraumatic neurotransmitter-linked receptor-coupled signal transduction contributes to post traumatic ischemic hypersensitivity by manipulating upregulated receptor systems with various moderate hypothermia applications before or after trauma; b) altered posttraumatic protein kinase activity contributes to altered posttraumatic receptor-coupled signal transduction by manipulation with various moderate hypothermia applications before or after trauma. These hypotheses will be tested by administering moderate hypothermia before or after TBI and evaluating hippocampal CA1 neuronal death, spatial memory, hippocampal EAA levels, glutamate agonist-induced PI hydrolysis, and SDS-PAGE separation/immunoblots of PKC isoforms.